Peripheral Chromatin’s Role in Nuclear Mechanics and Morphology through Multiscale Modeling
Abstract:
Nuclear morphology and mechanics critically influence cellular function and are altered in numerous diseases, including progeria, muscular dystrophy, and cancer. In addition, these critical nuclear features also change throughout the cellular differentiation. While experimental evidence implicates chromatin organization—particularly heterochromatin localized at the nuclear periphery—in shaping nuclear rigidity and form, the underlying physical mechanisms remain poorly defined.
We employ multiscale polymer-physics based computational approaches to bridge that gap. First, polymer physics simulations of a coarse-grained nuclear model, validated against micromechanical measurements and chromatin conformation data, reveal that nuclear stiffness increases when heterochromatin is tethered to the lamina and further enhanced by potential heterochromatin crosslinkers such as HP1α—phase segregation of chromatin into active and passive portions alone seems to have minimal impact on the nuclear rigidity. Cumulatively, heterochromatin tethering and crosslinks appear as a fundamental mechanism connecting nuclear and chromatin deformations, suggesting a mechano-regulatory mechanism. Second, using our composite polymer–elastic shell simulation framework, we also show that while higher chromatin density stabilizes nuclear shape, increased peripheral heterochromatin interactions paradoxically promote shape fluctuations via a “wetting”-like mechanism—suggesting that chromatin accumulation at the periphery may drive morphological instability.
Together, these findings propose a unified model in which heterochromatin’s tethering and crosslinking at the nuclear boundary are key determinants of both nuclear mechanics and morphology. This unified framework integrates mechanical and morphological insights and extends current understanding of nuclear behavior across healthy and diseased states.